2-Acylaminomethyl-1,4-benzodiazepine derivatives and their salts and pharmaceutical compositions thereof

ABSTRACT

Novel 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives are disclosed which possess the Formula I ##STR1## wherein R 1  represents hydrogen, lower akyl, lower alkenyl or cyclopropylmethyl; 
     R 2  represents hydrogen, lower alkyl or lower alkenyl; 
     R 3  represents a group of the formula a, b, c or d; ##STR2## wherein R is hydrogen or C 1  -C 3  - alkyl; 
     R 4  is hydrogen, lower alkyl, lower alkoxy, nitro or halogen, and 
     R 4  &#39; is hydrogen or C 1  -C 4  - alkyl and the aromatic groups A and B may be unsubstituted or substituted by 1 to 3 substituents such as halogen, lower alkylthio, lower alkoxy, lower alkyl, hydroxy, nitro, trifluoromethyl or methylenedioxy or ethylenedioxy and optical isomers and acid addition salts of the compounds. In addition to psycho pharmacological, diuretic and antiarrhythmic properties, the novel compounds of Formula I possess primarily outstanding analgesic activities and are low in toxicity. The compounds are prepared by acylating 2-aminomethyl-1,4-benzodiazepine derivatives with corresponding carbonic acid derivatives. Furthermore, 2-azidomethyl-1,4-benzodiazepine derivatives are disclosed which provide valuable intermediates for the preparation of the compounds of Formula I yet also possess themselves pharmacological activities.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-acylaminomethyl-1,4-benzodiazepine derivatives, their salts andprocesses for their preparation and pharmaceutical compositions thereofand methods of treatment using same.

The German Offenlegungsschrift No. 2 353 187 discloses inter alia2-acylaminomethyl-1,4-benzodiazepine derivatives wherein the acyl groupis a lower alkanoyl. These compounds possess a primarily anti-convulsiveactivity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel2-acylaminomethyl-1,4-benzodiazepine derivatives and pharmaceuticalcompositions thereof which possess a novel pharmacological activityprofile.

In particular it is an object of the present invention to provide2-acylaminomethyl-1,4-benzodiazepine derivatives which possess stronganalgesic activities in addition to psycho pharmacological, diuretic andantiarrhythmic properties. It is a further object of the presentinvention to provide such compounds and pharmaceutical compositionsthereof which are low in toxicity and exhibit a high therapeutic index.

It is a further object of the present invention to provide processes forpreparing such novel 2-acylaminomethyl-1,4-benzodiazepine derivativeswith improved pharmacological properties.

It is a further object of the present invention to provide novel2-azidoaminomethyl-1,4-benzodiazepine derivatives which are usefulintermediates in the preparation of the novel2-acylaminomethyl-1,4-benzodiazepine derivatives of the presentinvention and which themselves possess valuable pharmacologicalproperties.

In order to accomplish the foregoing objects according to the presentinvention, there are provided novel2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives of theFormula I ##STR3## wherein R₁ represents hydrogen, lower alkyl, loweralkenyl or cyclopropylmethyl,

R₂ represents hydrogen, lower alkyl or lower alkenyl,

R₃ represents a group of the formula a, b, c, or d ##STR4## wherein R ishydrogen or C₁ -C₃ -alkyl, R₄ is hydrogen lower alkyl, lower alkoxy,nitro or halogen, in particular chlorine or bromine, and R₄ ' ishydrogen or C₁ -C₄ -alkyl, and the aromatic groups A and B independentlyfrom each other each may be unsubstituted or be substituted by 1 to 3substituents selected from the group consisting of halogen, loweralkythio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl,or be substituted at two adjacent carbon atoms by methylenedioxy orethylenedioxy, and optical isomers and pharmaceutically-acceptable acidaddition salts thereof.

The compounds exhibit valuable pharmacological properties. In particularin addition to psycho pharmacological, diuretic and antiarrhythmicproperties, these compounds primarily exhibit strong analgesicactivities due to which they are useful in the treatment of pains.

According to the present invention, there are further providedpharmaceutical compositions comprising an analgesically effective amountof the above-defined compounds and a pharmaceutically acceptablediluent.

According to the present invention, there are further provided processesfor preparing the compounds of Formula I in good yields.

According to the present invention, compounds of Formula I can beprepared by acylating an amino compound of Formula II ##STR5## whereinA, B, R₁ and R₂ are as defined above or an acid addition salt thereofwith a reactive carbonic acid derivative of Formula III ##STR6## whereinR₃ is as defined above and Y represents hydroxy, halogen, lower alkoxy,or a group O--CO--Z wherein Z represents R₃ or lower alkoxy.

Subsequently, compounds of Formula I wherein R₂ represents hydrogen maybe alkylated into compounds of Formula I wherein R₂ represents loweralkyl. Also chloro, bromo or nitro substituents may be introduced intothe phenyl ring A of compounds of Formula I subsequent to the aboveacylating reaction.

The compounds of Formula I may be recovered from the respective reactionsolutions in the form of optical isomers or of racemic mixtures in formof the free bases or in form of the acid addition salts. Acid additionsalts may be transformed into free bases and vice versa according toconventional methods. Racemic mixtures may be separated into the opticalisomers according to conventional methods.

According to the present invention there are further provided novel2-azidomethyl-1,4-benzodiazepine derivatives of Formula X ##STR7##wherein A, B and R₁ are as defined above.

The compounds of Formula X are novel and represent valuableintermediates for the preparation of compounds of Formula I.Additionally, the compounds of Formula X themselves exhibit valuablepharmacological properties, in particular, bronchal-dilating, sedativeand antiarrhythmic properties, due to which they are useful assedatives, broncholytic and antiarrhythmic agents.

Further objects, features and advantages of the present invention willbecome apparent from the detailed description of the invention whichfollows.

DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED EMBODIMENTS

It has been found that the above-defined compounds of Formula I possessthe above-mentioned pharmacological activities and at the same time arelow in toxicity and thus exhibit a high therapeutic index.

If in the compounds of Formula I, R₁ or R₂ represent lower alkyl oralkenyl, these groups may contain up to four carbon atoms and may bestraight or branched. Suitable such groups are methyl, ethyl, propyl,isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, tert.-butyl, allyl,2-butenyl or 3-butenyl.

If R₄ represents lower alkyl, this group may contain 1 to 4 carbon atomsand may represent one of the above-mentioned lower alkyl groups. Loweralkoxy may contain 1 to 4 carbon atoms and may be straight or branched.

The alkyl group within alkyl, alkylthio or alkoxy substituents of thephenyl groups A and/or B also may contain 1 to 4 carbon atoms and may beone of the above-mentioned groups. Methyl and ethyl substituents arepreferred in particular in the case of di- and tri- substitution of thephenyl ring. Suitable halogen substituents include fluorine, chlorineand bromine. In the case of substitution of the phenyl ring withalkylthio, nitro or trifluoromethyl, mono-substitution is preferred. Inthe case of substitution with halogen and/or alkyl and/or alkoxy orhydroxy, mono- and disubstitution are preferred. In the case of loweralkoxy substituents, in particular methoxy, tri-substitution is alsofavorable.

It is known in the art (see for example German Offenlegungsschrift No. 2520 937 and No. 2 754 112) that 1,4-benzodiazepine derivatives which aresubstituted in the 2-position possess valuable pharmacologicalproperties and are low in toxicity. In particular, the known compoundsinfluence specifically the central nervous system. The effect of theseknown compounds are such that due to their anxiolytic andanti-aggressive properties, they present useful therapeutic agents forthe treatment of these symptoms in humans.

It is surprising that the novel 2-acylaminomethyl-1,4-benzodiazepinederivatives of the present invention possess a novel and differentpharmacological activity profile in that they possess outstandinganalgesic activities in addition to psycho pharmacological, diuretic andantiarrhythmic properties and are low in toxicity. The compounds ofFormula I exhibit analgesic activities in various standard tests insmall rodants and in monkeys.

The compounds of Formula I according to the present invention are usefulas analgesics in the treatment of pain due to their outstandinganalgesic activities which can be demonstrated by their capability toincrease the pain threshold in mammals.

This analgesic activity has been evaluated in two pharmacologicalstandard methods, the tail flick test in mice and the arthritis paintest in rats.

DESCRIPTION OF THE PHARMACOLOGICAL TEST METHODS 1. Determination of theMinimal Toxic Dose

Maximum doses of 300 mg/kg of the test compound are administered orallyto three male mice having a weight of 20-25 g and toxicity symptoms arecarefully observed for a period of three hours. Furthermore, over aperiod of 24 hours from the administration all symptoms and deaths areregistered. Side-symptoms are also observed and registered. Depending ontheir water solubility, the test compounds are administered either inform of aqueous solutions or in form of suspensions without the use ofsolvents. In order to maintain a stable suspension of the test compound,one drop of Tween-80 can be added and the mixture can be mechanicallyhomogenized. In the case of compounds where deaths or toxic symptomshave been observed, additional mice are treated with decreasing dosesuntil a dose is reached at which no toxic symptoms occur. The lowestdose which causes toxic symptoms is considered the minimal toxic dose.

2. Arthritis Pain Test in Rats

Male rats having a weight of from 160 to 180 g are anesthetized by smalli.p. injection of 20 mg/kg of sodium pentobarbital and 0.1 ml of asuspension of mycobacterium smegmae (SI 043) in liquid paraffin (0.6 mgmycobacterium/0.1 ml of oil) are injected intracutaneously into the leftrear paw. Fourteen days later when a marked secondary arthritis hasdeveloped in particular in the right rear paw, the effect of the testcompound is evaluated. A control-reading is taken 30 minutes prior toadministration of the test compound by bending the foot joint of theright rear paw three times and counting the number of squeakings. Ratswhich do not react are eliminated from the test. Three hours after oraladministration of the test compound the bending of the joint isrepeated. Animals which squeak only once or not at all are considered tobe protected against pain. Between about 9 and 20 rats are used per doseand the ED₅₀ (95% reliability) is determined according to the method ofLitchfield and Wilcoxon (1949). The dose which provides protection in50% of the treated animals is taken as ED₅₀.

3. Tail Flick Test in Mice

This test is carried out according to the method described by D'Amourand Smith (1941), yet fed male and female mice having a body weight of16 to 25 g are used instead of rats. Thirty minutes prior to treatmentwith the test compound, each mouse is placed separately in a cylindricalcontainer in such a manner that it cannot turn itself or move forward.Its tail is positioned in a narrow groove projecting out of thecontainer. A certain point of the tail of each animal (about 35 mmbeyond the root of the tail) is subjected to the heat beam of a lamp ofknown strength and temperature which is positioned directly under thetail. The number of seconds which pass before the mouse moves its tailout of the light beam is determined twice, once 30 minutes and once 15minutes prior to subcutaneous administration of the test compound (10mg/kg). Mice which show a reaction time differing more than 25% areeliminated from the test. The reaction time is again determined 15minutes and 30 minutes after the treatment and an increase of thereaction period of more than 75% of the average values prior totreatment in the same animal is considered as showing an analgesiceffect. The ED₅₀ (95% reliability) of each test compound 30 minutesafter administration is evaluated according to the method of Litchfieldand Wilcoxon (1949). The dose which increases the reaction time ascompared to the reaction time prior to treatment for more than 75% in50% of the animals is considered as ED₅₀.

The following compounds were tested according to the foregoing tests:

1.1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(Sesquitartrate/hemiisopropylate)

2.1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride/semihydrate)

3.8-methoxy-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

4.8-methoxy-1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

5.8-methoxy-1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

6.8-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

7.1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

8.1,7,8-trimethyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

9.8-methoxy-1-methyl-2-[(5-methylthiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

10.1,7-dimethyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(dihydrochloride)

11.1,7-dimethyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

12.1-methyl-2-[(5-methylthiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride; 0.4 acetone)

13.8-ethoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride; 0.5 water; 0.5 acetone)

14.1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-(3-methoxyphenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

15.7-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(sequihydrochloride; 0.3 water)

16.1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-(3-methoxyphenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

17.1-ethyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride; 0.15 water)

18.1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

19.1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

20.1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

21.1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

22.1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-2,3-dihydro-1,4-benzodiazepine

23.8-methoxy-1-methyl-2-[(3-methylthiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

24.7,8-methylenedioxy-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

25.7,8-methylenedioxy-1-methyl-2-[furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

26.7,8-methylenedioxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

27.8-methoxy-1-methyl-2-[(5-bromothiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

28.2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

29.8-methoxy-1-methyl-2-nicotinoylaminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(dihydrochloride; 0.4 water; 0.8 acetone)

30.8-methoxy-1-methyl-2-picolinoylaminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(1.8 hydrochloride)

31.8-methoxy-1-methyl-2-[(5-methylfurane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

32.7,8-methylenedioxy-1-methyl-2-[(5-methylthiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

33.8-methoxy-1-methl-2-[(1-methylpyrrol-2-carbonyl)-aminomethyl]-5-phenyl-1H-2.3-dihydro-1,4-benzodiazepine(hydrochloride)

34.8-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(4-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

35.8-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(2-trifluoromethylphenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

36.1-methyl-2-[(1-methylpyrrol-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

37.8-chloro-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

38.8-fluoro-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

39.8-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

40.8-methoxy-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

41.7,8-methylenedioxy-1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

42.8-methoxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(3-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

43.8-fluoro-1-methyl-2-[(5-methylthiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

44.7,8-ethylenedioxy-1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

45.1,7-dimethyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(1.4 hydrochloride; 0.5 water; 0.2 ethylacetate)

46.8-methoxy-1-methyl-2-[(5-bromothiophene-2-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

47.8-methoxy-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-4-(4-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

48.8-methoxy-1-methyl-2-[(5-bromothiophene-2-carbonyl)-aminomethyl]-5-(3-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

49.8-methoxy-1-methyl-2-[(5-bromothiophene-2-carbonyl)-aminomethyl]-5-(4-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine(hydrochloride)

The results of the pharmacological tests are given in the table below.

The results show that the compounds of the present inventionconsiderably increase the pain threshhold in mammals and humans.Accordingly, the compounds of the present invention are valuableanalgesics for the treatment of all types of pain. The administereddoses can vary depending on the type of the compound, the mode ofadministration and the treated condition. Suitable doses for largermammals may vary in the range of between about 0.1 and about 100 mg/kg.

    ______________________________________                                                             Tail Flick  Arthritis Pain                                         MDL        Test        Test                                         Compound  (mouse)    (mouse) s.c.                                                                              (Rat) p.o.                                   NO.       p.o. mg/kg ED.sub.50 mg/kg                                                                           ED.sub.50 mg/kg                              ______________________________________                                        1         >300       2.8         13                                           2         >300       2.8         32                                           3         >200       5.3         20                                           4         >200       7.0         21                                           5         >200       2.4         15                                           6          >50       2.8         9                                            7         >200       0.22        19                                           8         >200       8.0         14                                           9         >200       5.6         14                                           10        >300       3.2         32                                           11        >300       1.2         30                                           12        >300       2.8         10                                           13        >200       6.0         15                                           14        >300       1.6         32                                           15        >300       8.5         32                                           16        >300       0.5         32                                           17        >200       2.6         22                                           18        >300       4.1         18                                           19        >300       0.56        13                                           20        >300       1.1         18                                           21        >300       6.2         13                                           22                   0.44        14                                           23                   7.2         25                                           24                   3.8         10                                           25                   <5.6        <32                                          26                   2.0         <5.6                                         27                   >5.6        <32                                          28                   4.2         >32                                          29                   4.0         30                                           30                   7.0         >32                                          31                   4.4         30                                           32                   5.6         <18                                          33                   1.0         < 18                                         34                   2.1         5.6                                          35                   1.0         <18                                          36                   2.1         >18                                          37                   1.2         >18                                          38                   0.32        <18                                          39                   0.7         <10                                          40                   1.2         <18                                          41                   2.1         5.6                                          42                   5.6         <18                                          43                   5.6         <18                                          44                   >5.6        <18                                          45                   3.8         <18                                          46                   5.6         <18                                          47                   .32         <18                                          48                   >5.6        <18                                          49                   >5.6        <18                                          ______________________________________                                    

For the above-described medical applications the compounds of Formula Ican be used in the form of free bases as well as in the form ofpharmaceutically acceptable acid addition salts, that is, salts withsuch acids the anions of which are non-toxic at the dosage in question.Furthermore, it is advantageous to use such salts for the medicalapplications which are readily crystallizable and are not or onlyslightly hydroscopic. Examples of acids which are suitable forsalt-formation with compounds of Formula I are the following:hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methylsulfonic acid, ethylsulfonic acid, benzene sulfonic acid,p-toluene sulfonic acid, citric acid, acetic acid, lactic acid, succinicacid, maleic acid, furmaric acid, malic acid, tartaric acid, benzoicacid, phenylacetic acid and mandelic acid.

According to a feature of the present invention, there are furtherprovided pharmaceutical compositions containing an effective amount ofat least one of the compounds of Formula I or their pharmaceuticallyacceptable salts. The amount of active ingredient per dosage unit formmay vary between about 0.1 and about 100 mg whereby the dosage is chosendepending on the type of species to be treated and the requirement for agiven individual treatment. Generally, compositions for parentaladministration would contain lower amounts of active ingredient thancompositions for oral application. The compounds of Formula I may beapplied alone or in combination with pharmaceutically acceptable carriermaterials and/or adjuvants in many different dosage forms. For example,formulations for oral application may be in the form of solidformulations such as tablets, capsules, powders, granulates, coatedtablets and the like. Suppositories can also be used. Solid formulationsmay comprise conventional pharmaceutically acceptable inorganic carriermaterials such as talcum or an organic carrier material such as lactoseor starch. Conventional pharmaceutical adjuvants such as magnesiumstearate (as lubricant) may also be included. Liquid formulations suchas solutions, suspensions, or emulsions may comprise conventionalpharmaceutical diluents such as water, vaseline, suspending agents suchas polyoxyethylene glycols and the like. Furthermore, conventionaladjuvants such as preserving agents, stabilizing agents and emulsifiersmay be added.

According to the present invention the2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives ofFormula I are prepared by acylating an amino compound of Formula II oran acid addition salt thereof with a carbonic acid or a reactivecarbonic acid derivative of Formula III. The acylation can be effectedin a conventional manner. Suitably, the acylation is carried out in aninert solvent at a temperature of between about -30° C. and the boilingpoint of the solvent under normal atmospheric pressure or under elevatedpressure.

If a carbonic acid halogenate or a carbonic acid anhydride is used as anacylating agent, the reaction suitably is carried out in the presence ofan acid-binding agent such as an alkali metal carbonate or alkali metalhydroxide such as potassium carbonate, sodium carbonate or potassiumhydroxide or an organic tertiary amine for example triethylamine,tripropylamine, tributylamine, or pyridine. 4-dimethylaminopyridine or4-pyrrolidinopyridine also are very suitable. An excess of such tertiaryamines may additionally serve as an inert solvent.

Examples of suitable inert solvents include methylene chloride,chloroform, acetone, methylisobutylketone, tetrahydrofurane, dioxane,benzene, toluene, xylene, or chlorobenzene.

If carbonic acid esters, that is compounds of Formula III wherein Yrepresents lower alkoxy, are used as acylating agents, the reactionsuitably is carried out in a closed vessel. An excess of the carbonicacid ester may serve as a solvent. The reaction can be catalyzed byaddition of a metal alkylate, for example, by addition of aluminumisopropylate.

If a compound of Formula III is used wherein Y is halogen, suchcompounds of Formula III wherein Y is chlorine are particularlysuitable.

The novel compounds of Formula I also can be prepared by reacting acompound of Formula II wherein A, B, R₁ and R₂ are as defined above witha carbonic acid of the Formula IV ##STR8## wherein R₃ is as definedabove. This reaction is suitably carried out in an inert solvent attemperatures of from about -30° C. to boiling temperature of the solventin the presence of a suitable coupling agent such asdicyclohexylcarbodiimide, carbonyldiimidazol or the like. Preferably thereaction is carried out at a temperature of from about -30° to about+30° C. in an inert solvent such as methylene chloride, chloroform,benzene, or toluene.

Resulting compounds of Formula I wherein R₂ represents hydrogen cansubsequently be converted into the corresponding N-alkyl compounds byalkylation in a conventional manner. For example, such an alkylation canbe effected by replacing the hydrogen in a compound of Formula I whereinR₂ is hydrogen by a metal by reacting the compound of Formula I with ametallating agent in a suitable inert solvent and subsequently reactingthe metallated compound with an alkyl halogenide, alkylsulfate oralkylsulfonic acid ester.

The metallating reaction as well as the alkylation can be carried out attemperatures of from about -80° C. to boiling temperature of thesolvent.

Suitable metallating agents are, for example, sodium hydride,lithiumbutyl, lithiumphenyl, sodiumamide, lithiumdiisopropylamide, andalso sodiumalkoxide and thallium-I-alkoxide.

Suitable inert solvents can be chosen depending on the metallating agentwhich is used. Examples of suitable such solvents include diethylether,tetrahydrofurane, dioxane, benzene, toluene, dimethylformamide,dimethylsulfoxide, and in the case of metal alkoxides also thecorresponding alcohols, that is methanol in the case of methylalcoholates and ethanol in the case of ethyl alcoholates.

By means of the foregoing processes, the compounds of Formula I areobtained in racemic form. The present invention includes the compoundsof Formula I in the form of racemic mixtures as well as in opticallyactive forms. The optically active compounds can be obtained fromracemic mixtures of compounds of Formula I in conventional manner bysalt formation with suitable optically active acids and subsequentfractionated crystallization of the optically active antipodes of theresulting salts (see S. W. Willen, A. Collet, J. Jacques, Tetrahedron33, (1977) 2725-2736). Examples of suitable optically active acidsinclude tartaric acid, O,O'-dibenzoyl tartaric acid, mandelic acid,di-O-isopropylidene-2-oxo-L-gulonic acid. The obtained salts can betransformed into the free bases which, if desired, subsequently can betransformed into pharmacologically acceptable salts. The racemicmixtures, as well as the optically active isomers and the acid additionsalts can be purified by recrystallization from solvents such as loweralkyl alcohols and/or ethers.

Yet the separation of racemic mixtures into the optically activecompounds may also be performed at a suitable primary reaction step.

The preparation of the 2-aminomethyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula II which are used as starting materials, can bedone in a known manner according to processes which are disclosed inGerman Offenlegungsschrift No. 2 221 558.1-acyl-2-hydroxy-1,3-diaminopropane compounds are used as startingmaterials for compounds of Formula II and can be prepared according tothe method disclosed in German Offenlegungsschrift Nos. 2 221 558, 2 314993, 2 270 915 and 2 720 968.

The 2-hydroxy-1,3-diaminopropane compounds of Formula V ##STR9## whereinR₁ and A are as defined above can be reacted with an optionallysubstituted benzoylchloride to obtain compounds of Formula VI ##STR10##wherein A, B and R₁ are as defined above.

The starting materials of Formula V can be prepared in the mannerdescribed by M. Chadwick et al in J. Med. Chem. 9, Page 874 (1966).

At this reaction stage, compounds of Formula VI wherein R₁ representshydrogen can subsequently be alkylated in conventional manner into thecorresponding N-alkyl compounds. This alkylation can be carried out forexample according to the methods of reductive carbonyl-amination whichare known in the art such as the Leuckart-Wallach or theEschweiler-Clarke reaction (see H. Krauch, W. Kunz, Reaktionen derOrganischen Chemie (1976) page 126 and 131) or by alkylation withdialkylsulfates (see Houben-Weyl XI/1 (1957), S. 207 ff).

The compounds of Formula VI which are obtained in the above-describedmanner can subsequently be cyclized by reaction withphosphoroxyhalogenides, preferably phosphoroxychloride in conventionalmanner for example as is known from German Offenlegungsschrift Nos. 2221 558, 2 314 993 and 2 520 937. Suitably the compounds of Formula VIor acid addition salts thereof are treated with a cyclizing agent at atemperature of between about 100° C. and 150° C. as is disclosed inGerman Offenlegungsschrift No. 2 520 937 and subsequently the resultingmixture of the two isomer compounds of Formula VII and Formula VIII##STR11## wherein A and B and R₁ are as defined above and X representshalogen, preferably chloride, is isolated.

The two isomeric compounds of Formula VII and Formula VIII are presentin the reaction mixture in varying proportions depending on the type ofsubstituents in the aromatic nuclei A and B as well as on the positionof such substituents. This, however, is of no importance for thesubsequent reaction of this mixture since both isomers yield compoundsof Formula II wherein A, B, R₁ and R₂ are as defined above in thesubsequent reaction step (see also Milkowski et al. Eur. J. Med. Chem.6, page 501-507 (1976)). Therefore, no time consuming separation oranalysis of the mixture of isomers is necessary.

Thus after roughly removing by-products yet without separation into theisomeric components, the mixture of isomeric compounds of Formula VIIand Formula VIII which is obtained as described above can be reactedwith an alkali metal imide, preferably potassiumphthalimide, in themanner described in German Offenlegungsschrift No. 2 353 187 forcompounds of the type of Formula VII to obtain 2-phthalimido compoundsof Formula IX ##STR12## wherein A, B and R₁ are as defined above. Theraw or optionally previously purified compound of Formula IX than can besplit in a conventional manner by reaction with hydrazine hydrate orwith diluted hydrochloric acid to obtain compounds of Formula II whereinA, B and R₁ are as defined above and R₂ is hydrogen (see H. Krauch, W.Kunz, Reaktionen der Organischen Chemie (1976), page 638). Suitably thepreparation of the 2-phthalimido compound of Formula IX takes place in asolvent such as methanol, ethanol, isopropanol, dioxane, ordimethylformamide with or without addition of potassium iodide ascatalyst at temperatures of from about 50° to about 130° C.

The splitting reaction of compounds of Formula IX into compounds ofFormula II wherein R₂ is hydrogen suitably is carried out in a loweralkyl alcohol such as methanol, ethanol, isopropanol, t-butanol or waterat temperatures of from about 20° to about 120° C., preferably at theboiling temperature of the solvent.

The mixture of isomeric compounds of Formula VII and Formula VIII alsocan be transformed into compounds of Formula II wherein R₂ in additionto hydrogen also may have the above-given meaning other than hydrogen byreacting the isomeric mixture with ammonium hydroxide whereby compoundsof Formula II wherein R₂ is hydrogen are obtained or with a suitableprimary amine such as, for example, methylamine, ethylamine,propylamine, butyamine, allylamine, or cyclopropylmethylamine to obtaincompounds of Formula II wherein R₂ has a meaning other than hydrogen.The reaction can be carried out as is described in GermanOffenlegungsschrift No. 2 221 558 for compounds of the type of FormulaVII with or without a solvent at normal atmospheric pressure or atelevated pressure at temperatures of from about 20° to about 150° C.Suitably an excess of amine may serve as a solvent for the reaction, yetinert solvents such as water, methanol, ethanol, isopropanol, t-butanol,dioxane, benzene, toluene, xylene may also be used.

According to a modification of the above reaction instead of ammoniumhydroxide or of a primary amine an alkali metal salt thereof is reactedwith the mixture of isomeric compounds of Formula VII and Formula VIII.Suitable metals are in particular lithium and sodium. Suitably an excessof ammonia or of the corresponding primary amines serve as inertsolvent. Yet other inert solvents such as tetrahydrofurane, dioxane,benzene, and toluene also can be used. The alkali metal salts may beformed in situ or may be added in solid form. Suitable temperatures forthe reaction are from about -50° to about 150° C.

According to the novel embodiment of the preparation of compounds ofFormula I wherein A, B, R₁ and R₂ are as defined above according to thepresent innvention, compounds of Formula VII and/or Formula VIII arereacted with an alkali metal azide, preferably sodium or potassium azideto obtain 2-azidomethyl-1,4-benzodiazepine derivatives of Formula X##STR13## wherein A, B and R₁ are as defined above. Suitably thereaction takes place in an inert solvent at a temperature of from about-30° to 150° C. The compounds of Formula X can be isolated in the formof the free bases or in the form of acid addition salts thereof. Yet thecompounds also may be subjected to further reaction without separationfrom the reaction mixture optionally after removal of the solvent.

Examples of suitable solvents for the preparation of the azides ofFormula X include methylenechloride, chloroform, tetrahydrofurane,dioxane, dimethylformamide, dimethylsulfoxide,hexamethylphosphortriamide, methanol, ethanol, t-butanol, acetone, ormethylisobutylketone.

The compounds of Formula X are novel compounds which provide valuableintermediates for the preparation of compounds of Formula I.Furthermore, the compounds of Formula X themselves also possess valuablepharmacological properties. In particular, the compounds of Formula Xaccording to the present invention possess psycho pharmacologicalactivities which have been demonstrated in standard screening tests ofPANLABS Inc. in comparison with meprobramate and chlorodiazepoxide. Thecompounds further possess bronchodilatory properties which have beendemonstrated in guinea pig lungs through which a flow of compoundsolution is passed in comparison with aminophyllin, and antiarrhythmicproperties which are demonstrated after chloroform-induced arrhythmia inthe mouse heart in comparison to chinidine.

The pharmacological tests gave satisfactory results in a dosage range offrom about 0.5 to about 100 mg/kg. Accordingly, the compounds of FormulaX of the present invention are therapeutically useful as sedatives,broncholytic agents and antiarrhythmic agents.

By subsequent splitting of these compounds in known manner by reactionwith hydrazine hydrate/Raney-nickel with basic catalyzation or withpropanedithiol 2-aminomethyl-1,4-benzodiazepine compounds of Formula IIwherein R₂ is hydrogen are obtained. The reduction with hydrazinesuitably is carried out in an alcohol such as methanol or ethanol underaddition of a tertiary amine such as triethylamine at room temperature.The reduction with propanedithiol suitably is carried out by usingmethanol, ethanol, dimethylformamide or pyridine/water as a solvent.

The 2-aminomethyl compounds can be transformed into the desired 2-acylaminomethyl-1,4-benzodiazepine derivatives of Formula I as has beendescribed above.

It is especially noted at this point that for the above-describedreactions for the preparation of compounds of Formula II, IX and X themixture of isomeric compounds of Formula VII and VIII suitably is usedyet that it is evident to anyone skilled in the art that the mixture ofisomers also can be separated into its components which later canseparately be converted into compounds of Formula II, IX and X accordingto the above-described reaction.

Subsequent substitution of the nucleus A of the 1,4-benzodiazepinesystem by halogen or nitro substituents is possible in a conventionalmanner as has already been described in German Offenlegungsschrift No. 2221 558. Such substitution suitably can be effected on compounds ofFormula I, VII, IX and X. N-chlorosuccinimide or N-bromosuccinimide mayfor example serve as a halogenating agent.

For introducing the nitro substituent conventional nitrating agents canbe used such as KNO₃ in H₂ SO₄ or copper-II-nitrate-trihydrate in aceticacid anhydride.

Starting materials of Formula II wherein R₁ is hydrogen with theexception of those wherein A and/or B are substituted by alkyloxy oralkylthio may also be prepared by dealkylating a compound of Formula IIwherein R₁ is alkyl, preferably methyl, by reaction with hydrogeniodideacid. The reaction is carried out in concentrated hydrogeniodide acid attemperatures of between about 50° and about 100° C.

The compounds of Formula I which are obtained by the processes accordingto the present invention may be isolated in the form of the free basesor, if desired, may be converted into acid addition salts with inorganicor organic acids in conventional manner. For example, in order to obtainthe salt, the desired acid is added to a solution of the compound ofFormula I in a suitable solvent. Preferably, an organic solvent is usedwherein the resulting salt is unsoluble so that it can be separated byfiltration. Examples of such solvents include ethanol, isopropanol,ether, acetone, acetic acid ethyl ester, acetone/ether, acetone/ethanol,ethanol/ether.

The following examples are intended to illustrate the preparation of thenovel compounds of Formula I and of pharmaceutical compositions thereofas well as of the novel intermediate compounds of Formula X but are notintended to limit the scope of the present invention in any way.

The chemical structure of the novel compounds has been verified byspectroscopic analysis, in particular by exact analysis of theNMR-spectra. In the following table the melting points of themonohydrochlorides of the compounds are given where no other data arerecited. The presence of any included amounts of water, acetone, ethanolor the like is noted.

Where no salt is given, the amide--C═O band in the IR spectrum of theoily base in the range of 1630-1650 cm⁻¹ is determined (Perkin-Elmer IRspectrophotometer 157 G).

EXAMPLE 11-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

(a) A mixture of 202 g of N₁ -benzoyl-N₂ -methyl-N₂-phenyl-2-hydroxy-1,3-diaminopropane and 1000 ml of phosphoroxychlorideis heated under reflux for a period of 2.5 hours. Subsequently theexcess phosphoroxychloride is distilled off and the residue is dissolvedin 1000 ml of chloroform. The chloroform solution is agitated with 1000ml of ice/water, the organic phase is separated and is washed five tosix times with 200 ml of water each. Subsequently the organic phase isagitated with 1200 ml of sodium hydroxide solution (20%) and then washedwith water until neutral reaction. The chloroform phase then is driedand decolorized by addition of sodium sulfate and γ-aluminum oxide(aluminum oxide "Giulini"). After filtering the solution is evaporated.

(b) The resulting oilybase (202 g) which comprises a mixture of1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and1-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine isintroduced into 1300 ml of methanol, 138.5 g of potassium phthalimideand 38.2 g of potassium iodide are added and the mixture is heated underrefluxed for 22 hours. Subsequently, the methanol is distilled off and500 ml of chloroform are added to the residue. Insoluble components arefiltered off and discarded. The filtrate is separated and 256.4 g of1-methyl-2-phthalimidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineare obtained in the form of an oily residue.

Without any further purification, this residue is added to 71.1 g ofhyrazine hydrate in 3200 ml of ethanol and the reaction mixture isheated under reflux for 4.5 hours. Then 330 ml of concentratedhydrochloric acid (32%) are added and the reaction mixture is furtherheated under reflux for an additional 15 minutes. After cooling theformed crystals are filtered off. The filtrate is subsequentlyevaporated under vacuum. 1500 ml of water are added to the residue andthe mixture is again filtered. Hydrochloric acid is added to thefiltrate and, any non basic components are removed from the mixture byagitating with methylene chloride. The acid aqueous phase is renderedalkaline by addition of concentrated sodium hydroxide solution (50%).The base which separates in the form of an oil is dissolved inmethylenechloride. The solution is washed several times with sodiumchloride solution (10%), dried over sodium sulfate and filtered.

After distilling off the solvent, 127.3 g of residue are obtained andare dissolved in ether and filtered. A saturated solution of hydrogenchloride in ether is added to the filtrate. The formed crystals arefiltered off, washed with ether and are stirred with cold acetonecontaining a small amount of isopropanol. The crystals are filtered offunder suction, washed with acetone and dried.

108.5 g of1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinedihydrochloride having a melting point of 209° to 213° C. are obtained.

(c) 13.4 g of1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine(obtained as described above) and 7.65 ml of triethylamine are dissolvedin 320 ml of methylene chloride. Under cooling and agitation with ice asolution of 8.12 g of thiophen-2-carboxylic acid chloride in 20 ml ofmethylene chloride is added. Subsequently, the reaction solution isallowed to stand at room temperature over night. Then the solution iswashed with water, sodium carbonate solution (10%) and saturated sodiumchloride solution, is dried over sodium sulfate and filtered. Afterdistilling off the solvent 21 g of material are obtained and purified,chromotographically, using 300 g of aluminum oxide activity level I(standard Merck) as absorbent and eluating successively withcyclohexane, toluene, methylene chloride and ethanol. The toluene- andmethylene chloride eluate (19.4 g) are added to each other and dissolvedin ether. A solution of 7.8 g of racemic tartaric acid in ethanol isadded. The tartrate is precipitated by addition of ether and afterfilteration is recrystallized from ethanol at a temperature of -70° C.to -60° C.

10 g of1-methyl-2-[(thiophene-2-carbonyl)aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinetartrate×0.4 mol of ethanol having a melting point of 110° to 125° C.(decomposition) are obtained. The free base has a melting point of112°-115° C.

EXAMPLE 21-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

(a) A mixture of 68.4 g of the cyclization mixture obtained according toExample 1 (a) and containing1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and1-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine, 47.2 g ofsodium azide and 420 ml of dimethylformamide is heated to 100° C. for aperiod of 4 hours. Subsequently, the dimethylformamide is distilled offunder vacuum and 300 ml of toluene and 200 ml of water are added to theresidue. The organic phase is separated, washed with sodium chloridesolution (10%), dried over sodium sulfate and filtered. The solvent isdistilled off and 56.1 g of raw product are obtained as residue. Theresidue is dissolved in ether and a saturated solution of hydrogenchloride in ether is added. The precipitated crystals are filtered offand are recrystallized from acetone/isopropanol.

36.7 g of1-methyl-2-azidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 181°-183° C. are obtained.

(b) 21.7 g of1-methyl-2-azidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride are dissolved in 325 ml of methanol. 9.5 ml oftriethylamine and subsequently 13.5 ml of hydrazine hydrate are added.Then 10 g of Raney-nickel are added portionwise to the reaction solutionunder agitation at room temperature. After three hours, the addition ofRaney-nickel is completed The reaction mixture is agitated for anotherone hour, then the Raney-nickel is filtered off. The filtrate isevaporated under vacuum, the residue is dissolved in methylene chlorideand the solution is washed with water and sodium chloride solution(10%). Subsequently, the organic phase is dried over sodium sulfate,filtered and evaporated. 17.1 g of1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine areobtained. Its dihydrochloride has a melting point of 209° to 213° C.

(c) 13.5 g of thiophene-3-carboxylic acid are dissolved in 300 ml ofmethylene chloride and are cooled to a temperature of 0° to 5° C. Then14.5 ml of triethylamine are added and subsequently 11.2 ml ofchloroformic acid ethyl ester are added dropwise within a period of 5 to10 minutes. Then the reaction solution is agitated for another 30minutes at the temperature of 0° to 5° C. and subsequently is addeddropwise and under cooling to a solution of 27.9 g of1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine in 200ml of methylene chloride in such a manner that the temperature isretained at between 0° to 5° C. Subsequently, the reaction solution isagitated for another four hours at room temperature, then is washed withwater, diluted ammonium hydroxide solution (10%) and sodium chloridesolution, dried over sodium sulfate and filtered. The solvent isdistilled off. 37.8 g of raw product are obtained.

The raw base is dissolved in ether and a saturated solution of hydrogenchloride in ether is added. The precipitated crystals are filtered offand are heated to boiling temperature in a mixture of acetone/aceticacid ethyl ester. 21.9 g of1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 234°-237.5° C. are obtained.

EXAMPLE 37-nitro-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

2.5 g of1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineare dissolved in 9 ml of acetic acid anhydride. 1.58 g of copper(II)-nitrate.3H₂ O are added portionwise at a temperature of 30°-35° C.After addition of the copper salt is completed, the reaction mixture isadded to a saturated sodium bicarbonate solution and ice. The alkalinesolution is extracted with 50 ml of methylene chloride and the organicphase is worked up in a conventional manner.

The free base is transferred into the hydrochloride. 0.7 g7-nitro-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 254°-256° C. are obtained.

EXAMPLE 47-nitro-1-methyl-2-[(thiophene-2-carbonyl)aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

A solution of 4.5 g of potassium nitrate in 8 ml of concentratedsulfuric acid is added at a temperature of 5° C. to a solution of 5.2 gof 1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine in50 ml of glacial acetic acid. The reaction mixture is agitated at roomtemperature for a period of one hour and then is poured onto 200 g ofice, is rendered alkaline by addition of diluted sodium hydroxidesolution (20%) and is extracted with methylene chloride. Subsequently,the organic phase is washed with water until neutral reaction, is driedover sodium sulfate and filtered. After distilling off the solvent,7-nitro-1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineis obtained. Its hydrochloride having a melting point of 230°-240° C.

A mixture of 4.5 g of this compound, 50 ml of methanol and 2.7 g ofpotassium phthalimide and 800 mg of potassium iodide is heated underreflux. After the reaction mixture has been worked up in conventionalmanner, 4 g of7-nitro-1-methyl-2-phthalimidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineare obtained. These are heated under reflux in 200 ml of hydrochloricacid (24%) for a period of four hours. The reaction solution ispartially evaporated and sodium hydroxide solution is carefully addeduntil an alkaline reaction is reached. Then the raw reaction product (2g of7-nitro-1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine)is extracted with methylene chloride and isolated in a conventionalmanner. Without further purification, it is dissolved in 100 ml ofmethylene chloride and 0.65 g of triethylamine and subsequently undercooling with ice, a solution 0.93 g of thiophene-2-carboxylic acidchloride in 20 ml of methylene chloride are added. After the reactionmixture has been worked up in conventional manner, 1.8 g of7-nitro-1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 254°-256° C. are obtained.

EXAMPLE 57-chloro-1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiaepine

The mixture of 4.2 g of1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and1.95 g of N-chlorosuccinimide in 75 ml of methylenechloride is heatedunder reflux for a period of 24 hours. Then the reaction solution iswashed with water and dried over sodium sulfate. After filtering anddistilling off the solvent, 4.5 g of7-chloro-1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineare obtained. Its hydrochloride has a melting point of 110°-112° C.(from isopropanol).

A mixture of 4.0 g of this compound, 25 ml of methanol, 2.5 g ofpotassium phthalimide and 750 mg of potassium iodide is heated underreflux for 20 hours. Then the methanol is distilled off and 25 ml ofchloroform are added to the residue. The insoluble components arefiltered off and discarded. The filtrate is evaporated and 6.3 g ofresidue are obtained. A mixture of residue, 1.9 g of hydrazine hydrateand 100 ml of ethanol is heated under reflux for a period of four hours.Then 10 ml of concentrated hydrochloric acid (32%) are added and thereaction mixture is again heated under reflux for another 15 minutes.After cooling the precipiated crystals are filtered off and the filtrateis evaporated under vacuum. 50 ml of water are added to the residue andthe mixture is again filtered. The filtrate is acidified withconcentrated hydrochloric acid and is extracted with methylenechloride(100 ml). The base is separated in the form of an oil by addition ofconcentrated sodium hydroxide solution (50%) and is dissolved inmethylenechloride. The solution is washed with saturated sodium chloridesolution, dried over sodium sulfate and filtered. The solvent isdistilled off and 3.1 g of7-chloro-1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodizepineare obtained. This residue is dissolved in 80 ml of ethylenechloridewithout further purification and 1.05 g of triethylamine are added. Thena solution of 1.35 g of furan-2-carboxylic acid chloride in 10 ml ofmethylenechloride is added dropwise under cooling with ice and exclusionof moisture. Then the reaction mixture is agitated at room temperaturefor another two hours and is worked up in a conventional manner. Thefree base is transformed into its hydrochloride. 2.67 g of7-chloro-1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 235°-236.5° C. are obtained.

EXAMPLE 61-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-(2'-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine

12.5 g of1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepinedihydrochloride are dissolved in 160 ml of methylenechloride underaddition of 15.9 ml of triethylamine. Then a solution of 5.0 g offuran-3-carboxylic acid chloride in 50 ml of methylene chloride is addeddropwise under ice cooling. The reaction solution is agitated for 3hours at room temperature and then is worked up in a conventionalmanner. 9.0 g of the hydrochloride of the title compound having amelting point of 227°-228° C. are obtained.

EXAMPLE 78-methoxy-1-methyl-2-[(1-methylpyrrol-2-carbonyl)-aminomethyl]-5-(2'-chlorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine

9.2 g of8-methoxy-1-methyl-2-aminomethyl-5-(2'-chlorophenyl)-1H-2,3-dihydro-1,4-benzodiazepineare dissolved in 230 ml of methylenechloride and 4 ml of triethylamineare added. Then a solution of 4.0 g of 1-methylpyrrol-2-carboxylic acidchloride in 25 ml of methylenechloride are added dropwise under icecooling. After the addition is completed, the reaction mixture isimmediately worked up in a conventional manner. 2.4 g of thehydrochloride of the title compound are obtained which contain 0.66 molH₂ O and possess a melting point of 178°-225° C. (decomposition).

EXAMPLE 82-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

A mixture of 10 g of1-methyl-2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and 40ml of hydrogen iodide acid (67%) is heated to a temperature at 80° C.under agitation for a period of four hours. Subsequently, the reactionliquid is poured onto ice (500 g) and is carefully neutralized byaddition of solid sodium carbonate. After adding 50 ml of concentratedsodium hydroxide solution the base is extracted with methylenechloride.The organic phase is washed with saturated sodium chloride solution,dried over sodium sulfate and filtered. The solvent is distilled off and9 g of 2-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine areobtained as an oily base. The oily base is dissolved in 250 ml ofmethylenechloride under addition of 3.6 g of triethylamine. A solutionof 5.2 g of thiophene-2-carboxylic acid chloride in 25 ml ofmethylenechloride is added dropwise under agitation and cooling. Thereaction solution is agitated for two hours at room temperature and thenis worked up. 20 g of oily residue are obtained which is purifiedchromotographically using 200 g of aluminum oxide activity degree II asabsorbent and eluating with toluene. The eluate is collected in 200 mlfractions. The desired reaction product is enriched in fractions 10 to24. After evaporating the toluene, these fractions together aredissolved in 200 ml of methylene chloride. The methylenechloridesolution is stirred with 50 g of γ-aluminum oxide and filtered. Thefiltrate is evaporated and 14.2 g of raw product are obtained as residueand are recrystallized from toluene. 6.7 g of the title base having amelting point of 172°-174° C. are obtained.

EXAMPLE 91-methyl-2-[(thiophene-2-carbonyl)-N-methylaminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

7.6 g of1-methyl-2-[(thiophene-2-carbonyl)aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineare dissolved in 100 ml of tetrahydrofurane and 0.66 g of sodium hydride(80% in oil) are added under agitation. Then the reaction mixture iscooled to 5° C. and a solution of 1.36 ml of methyliodide in 10 ml oftetrahydrofurane is added slowly (about 30 minutes are used for thedropwise addition). Subsequently, the reaction solution is agitated fortwo hours at a temperature of 5° to 10° C. and then is diluted with 10ml of ice water in such an amount of toluene that after addition of morewater two phases are formed. The organic phase is washed with waterseveral times, dried over sodium sulfate and filtered. The solvent isdistilled off and 7.5 g of raw product are obtained.

The raw product is dissolved in 50 ml of ether and a separated solutionof 7.8 g of D,L-tartaric acid in ethanol is added. By further additionof ether the tartrate is precipitated and is filtered off andrecrystallized from ethanol.

9 g of1-methyl-2-[(thiophene-2-carbonyl)-N-methylaminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinetartrate×0.4 mol of ethanol having a melting point of 110°-125° C. areobtained.

EXAMPLE 101-methyl-2-[(thiophene-2-carbonyl)-N-n-propylaminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine

A mixture of 10 g of the product which is obtained by cyclization withphosphoroxychloride from N₁ -benzoyl-N₂ -methyl-N₂-phenyl-2-hydroxy-1,3-diaminopropane according to Example 1 (a) and 100ml of n-propylamine is heated in an autoclave to a temperature of 80° C.for a period of 24 hours. After cooling the excess amine is distilledoff. Water and subsequently 50 ml of diluted sodium hydroxide solution(20%) are added to the residue and the mixture is extracted withmethylenechloride. The organic phase is washed with saturated sodiumchloride solution, dried over sodium sulfate and filtered. The solventis distilled off and 8 g of1-methyl-2-propylaminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepineis obtained as an oily residue.

This residue is dissolved in 150 ml of methylenechloride under additionof 2.6 g of triethylamine. A solution of 3.8 g of thiophene-2-carboxylicacid chloride in 20 ml of methylenechloride is added under agitation andcooling with ice. The reaction solution is agitated at room temperaturefor two hours and then is washed with water, sodium carbonate solution(10%) and saturated sodium chloride solution. After drying over sodiumsulfate and filtration the solvent is distilled off. The residue (9 g)is dissolved in ethanol, 2 mol of racemic-tartaric acid are added andthe product is crystallized from ethanol/ether. 7 g of the free base areobtained which crystallize with 1.6 mol of tartaric acid and 0.5 mol ofH₂ O. Melting point 108°-118° C. (decomposition).

According to Examples 1 to 10, the following compounds can be prepared:

1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula I wherein A, B are substituted and R₄ is definedas follows:

    ______________________________________                                                                       Melting Point °C.                       A         B           R.sub.4  Hydrochloride                                  ______________________________________                                        H         H           H        112-115 (Base)                                 8-Cl      H           H        240-242                                                                       1.5 HCl                                        7-F       H           H        224-227                                        8-F       H           H        232-236                                        7-CH.sub.3                                                                              H           H        219-224                                        6,8-di-CH.sub.3                                                                         H           H        232-234                                        7,8-di-CH.sub.3                                                                         H           H        246-249                                        8-C.sub.2 H.sub.5                                                                       H           H        221-223.5                                      7-i-C.sub.3 H.sub.7                                                                     H           H        262-264                                        7-OCH.sub.3                                                                             H           H        150-157                                                                       . 0.5 H.sub.2 O                                8-OCH.sub.3                                                                             H           H        230.5-231.5                                    7,8-di-OCH.sub.3                                                                        H           H        243-245                                        6,8-di-OCH.sub.3                                                                        H           H        245-246.5                                      8-OC.sub.2 H.sub.5                                                                      H           H        195-197                                                                       . 1 acetone                                    7-n-OC.sub.3 H.sub.7                                                                    H           H        227-230                                                                       1.4 HCl                                        7,8-OCH.sub.2 O--                                                                       H           H        259-263                                        7,8-OC.sub.2 H.sub.4 O--                                                                H           H        265-276                                        8-SCH.sub.3                                                                             H           H        259-265                                        H         2-F         H        241-242                                        H         3-OCH.sub.3 H        205-208                                        H         2,6-di-OCH.sub.3                                                                          H        202-205                                        H         3,4-di-OCH.sub.3                                                                          H        218-220                                        7-CH.sub.3                                                                              2-F         H        238-249                                        8-OCH.sub.3                                                                             3-F         H        236-238                                        8-OCH.sub.3                                                                             4-F         H        226-229                                        8-OCH.sub.3                                                                             2-F         H        213-216                                        8-OCH.sub.3                                                                             2-Cl        H        220-229                                        8-OCH.sub.3                                                                             2-Br        H        229-232                                        8-OCH.sub.3                                                                             2-CF.sub.3  H        173-177                                        8-OCH.sub.3                                                                             3-CF.sub.3  H        224-227                                        8-OCH.sub.3                                                                             4-CF.sub.3  H        224-227                                        8-OCH.sub.3                                                                             2-CH.sub.3  H        229-232                                        7-F       3,4,5-tri-OCH.sub.3                                                                       H        201-203                                        7-CH.sub.3                                                                              3,4,5-tri-OCH.sub.3                                                                       H        178-182                                        7-Br      2-Cl        H        246-247.5                                      7-CF.sub.3                                                                              H           H        254-256                                        7,8-OCH.sub.2 O--                                                                       2-F         H        199-201                                                                       (Base)                                         H         H           5-C.sub.2 H.sub.5                                                                      192-195                                        8-OCH.sub.3                                                                             2-F         5-C.sub.2 H.sub.5                                                                      171-174                                        H         H           4-CH.sub.3                                                                             221-223                                                                       . 0.75 acetone                                 H         H           3-CH.sub.3                                                                             227-228                                        8-OCH.sub.3                                                                             H           3-CH.sub.3                                                                             226-227                                        7-n-OC.sub.3 H.sub.7                                                                    H           3-CH.sub.3                                                                             186-189                                        8-OCH.sub.3                                                                             2-F         3-CH.sub.3                                                                             161-165                                                                       . 0.5 H.sub.2 O                                8-OCH.sub.3                                                                             2-F         5-CH.sub.3                                                                             180-189                                                                       (decomp.)                                                                     . 0.25 H.sub.2 O                               8-OCH.sub.3                                                                             2-F         4-CH.sub.3                                                                             198-202                                                                       . 0.15 H.sub.2 O                               H         H           4-Br     202-205                                        H         H           5-Br     236-245                                        8-OCH.sub.3                                                                             H           5-Br     225-226                                        8-OCH.sub.3                                                                             2-F         5-Br     219.5-220.5                                    8-OCH.sub.3                                                                             3-F         5-Br     221-222                                        8-OCH.sub.3                                                                             4-F         5-Br     228-231                                        H         H           5-CH.sub.3                                                                             218-223                                                                       . 0.4 Acetone                                  8-F       H           5-CH.sub.3                                                                             238-240                                        7-OCH.sub.3                                                                             H           5-CH.sub.3                                                                             246-251                                        8-OCH.sub.3                                                                             H           5-CH.sub.3                                                                             231-233                                        8-OC.sub.2 H.sub.5                                                                      H           5-CH.sub.3                                                                             238-240                                        7,8-OCH.sub.2 O--                                                                       H           5-CH.sub.3                                                                             257-267                                        8-SCH.sub.3                                                                             H           5-CH.sub.3                                                                             229-232                                        7-CH.sub.3                                                                              2-F         5-CH.sub.3                                                                             238-247                                        7-F       3,4,5-OCH.sub.3                                                                           5-CH.sub.3                                                                             170-172                                        H         H           5-OCH.sub.3                                                                            Oil                                            H         H           5-OC.sub.2 H.sub.5                                                                     Oil                                            H         H           5-Cl     Oil                                            8-OCH.sub.3                                                                             4-F         5-CH.sub.3                                                                             Oil                                            8-OCH.sub.3                                                                             4-F         4-CH.sub.3                                                                             Oil                                            7,8-OCH.sub.2 O--                                                                       2-F         5-CH.sub.3                                                                             228-243                                        7,8-OCH.sub.2 O--                                                                       2-F         4-CH.sub.3                                                                             Oil                                            7,8-OCH.sub.2 O--                                                                       2-F         5-OCH.sub.3                                                                            218-223                                        H         2-F         5-OCH.sub.3                                                                            Oil                                            H         2-F         4-Br     204-208                                        ______________________________________                                    

1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula I, wherein A, and B are substituted and R₄ isdefined as follows:

    ______________________________________                                                                       Melting Point °C.                       A         B           R.sub.4  Hydrochloride                                  ______________________________________                                        7-CH.sub.3                                                                              H           H        244-245.5                                                                     2 HCl                                          6,8-di-CH.sub.3                                                                         H           H        227-229                                        7,8-di-CH.sub.3                                                                         H           H        245-247                                        8-C.sub.2 H.sub.5                                                                       H           H        209-212                                        7-i-C.sub.3 H.sub.7                                                                     H           H        247-252                                        7-OCH.sub.3                                                                             H           H        127-130                                                                       1.34 HCl . 0.45 H.sub.2 O                      8-OCH.sub.3                                                                             H           H        222-224                                        7,8-di-OCH.sub.3                                                                        H           H        227-229                                        8-OC.sub.2 H.sub.5                                                                      H           H        160-166                                                                       . 0.9 acetone                                  7-n-OC.sub.3 H.sub.7                                                                    H           H        227-230                                        7,8-OCH.sub.2 O--                                                                       H           H        264-269                                        8-SCH.sub.3                                                                             H           H        243-246                                        H         2-F         H        242-243                                        H         3-OCH.sub.3 H        205-207.5                                      H         3,4-di-OCH.sub.3                                                                          H        216-217                                        7-Br      2-Cl        H        259-263                                        7-F       3,4,5-tri-OCH.sub.3                                                                       H        219-223                                        7-CH.sub.3                                                                              3,4,5-tri-OCH.sub.3                                                                       H        184-187                                        H         3-CF.sub.3  H        231-232                                        8-OCH.sub.3                                                                             4-OCH.sub.3 H        218-222                                        7-Cl,8-OCH.sub.3                                                                        2-F         H        Oil                                            8-CH.sub.3                                                                              2-F         H        237-247                                        8-NO.sub.2                                                                              H           H        Oil                                            8-OC.sub.2 H.sub.5                                                                      2-F         H        227-237                                        8-i-OC.sub.3 H.sub.7                                                                    2-F         H        222-226                                        7,8-OCH.sub.2 O--                                                                       2-F         H        164-168                                                                       (Base)                                         6-OCH.sub.3                                                                             2-F         H        Oil                                            7-F,8-OCH.sub.3                                                                         2-F         H        Oil                                            6,7-OCH.sub.2 O--                                                                       2-F         H        Oil                                            H         2-F         H        Oil                                            H         4-CF.sub.3  H        Oil                                            6-OH      2-F         H        Oil                                            9-CH.sub.3                                                                              H           H        Oil                                            8-CH.sub.3                                                                              H           H        226-236                                        H         H           2-CH.sub.3                                                                             Oil                                            H         2-F         2-CH.sub.3                                                                             Oil                                            8-CH.sub.3,6-OCH.sub.3                                                                  2-F         H        Oil                                            ______________________________________                                    

1-methyl-2-[(furane-2-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula I, wherein A and B are substituted and R₄ isdefined as follows:

    ______________________________________                                                                        Melting Point °C.                      A         B            R.sub.4  Hydrochloride                                 ______________________________________                                        H         H            H        222-225                                       7-CH.sub.3                                                                              H            H        238-240                                       8-C.sub.2 H.sub.5                                                                       H            H        217.5-219                                     7-i-C.sub.3 H.sub.7                                                                     H            H        245-251                                       7-OCH.sub.3                                                                             H            H        219-222                                                                       . 0.25 H.sub.2 O                              6,8-di-OCH.sub.3                                                                        H            H        242-244                                       7,8-di-OCH.sub.3                                                                        H            H        242.5-244                                     7,8-OCH.sub.2 O--                                                                       H            H        258-265                                       8-SCH.sub.3                                                                             H            H        246-249                                       H         2-F          H        225-227                                       H         3-OCH.sub.3  H        195-197                                       H         3,4-di-OCH.sub.3                                                                           H        215-217                                                                       . 0.3 H.sub.2 O                               7-Br      2-Cl         H        237-239                                       7-F       3,4,5-tri-OCH.sub.3                                                                        H        168-172                                       7-CH.sub.3                                                                              3,4,5-tri-OCH.sub.3                                                                        H        191-197                                       7,8-di-CH.sub.3                                                                         H            H        241-244                                       6,8-di-CH.sub.3                                                                         H            H        232.5-234                                     H         H            5-CH.sub.3                                                                             196-198                                       7,8-OCH.sub.2 O--                                                                       2-F          5-CH.sub.3                                                                             246-259                                       8-OCH.sub.3                                                                             H            H        225-228                                       8-OCH.sub.3                                                                             H            5-CH.sub.3                                                                             228-230                                       7-n-OC.sub.3 H.sub.7                                                                    H            5-CH.sub.3                                                                             216-219                                       H         H            5-NO.sub.2                                                                             199-200                                                                       (base)                                        ______________________________________                                    

1-methyl-2-[(furane-3-carbonyl)-aminomethyl]-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula I, wherein A and B are substituted and R₄ is asdefined as follows:

    ______________________________________                                                                       Melting Point °C.                       A          B           R.sub.4 Hydrochloride                                  ______________________________________                                        H          H           H       135-137                                                                       (base)                                         7-Cl       H           H       251-253                                                                       1.1 HCl                                        8-Cl       H           H       229-231                                        7-F        H           H       224-226                                        8-F        H           H       235-236                                        7-CH.sub.3 H           H       224-226                                        7,8-di-CH.sub.3                                                                          H           H       243.5-247                                      6,8-di-CH.sub.3                                                                          H           H       231-232                                        8-C.sub.2 H.sub.5                                                                        H           H       201-204                                        7-i-C.sub.3 H.sub.7                                                                      H           H       243-246                                                                       . 0.2 H.sub.2 O                                7-OCH.sub.3                                                                              H           H       132-138                                                                       1.5 HCl . 0.3 H.sub.2 O                        8-OCH.sub.3                                                                              H           H       213-216                                        8-OC.sub.2 H.sub.5                                                                       H           H       147-152                                                                       . 0.5 H.sub.2 O .                                                             . 0.5 Acetone                                  7-n-OC.sub.3 H.sub.7                                                                     H           H       214-218                                        7,8-di-OCH.sub.3                                                                         H           H       240-241.5                                      7,8-OCH.sub.2 O--                                                                        H           H       201-204                                                                       (Base)                                         7,8-OCH.sub.2 CH.sub.2 O--                                                               H           H       267-275                                        8-SCH.sub.3                                                                              H           H       247-249                                        H          2-F         H       227-228                                        H          3-CF.sub.3,4-Cl                                                                           H       184-186                                                                       . 0.6 H.sub.2 O .                                                             . 0.3 Acetone                                  H          3-OCH.sub.3 H       183-186                                        H          2,6-di-OCH.sub.3                                                                          H       198-202                                        H          3,4-di-OCH.sub.3                                                                          H       215-217                                        7-CH.sub.3 2-F         H       236-243                                                                       1.4 HCl . 0.5 H.sub.2 O                                                       . 0.2 ethylacetate                             8-OCH.sub.3                                                                              2-Cl        H       220-222                                                                       . 0.5 H.sub.2 O                                8-OCH.sub.3                                                                              2-Br        H       228-233                                                                       . 0.5 H.sub.2 O                                8-OCH.sub.3                                                                              3-F         H       234-236                                        8-OCH.sub.3                                                                              4-F         H       229-232                                        8-OCH.sub.3                                                                              2-F         H       220-221                                        8-OCH.sub.3                                                                              2-CF.sub.3  H       219-222                                                                       . 1,3 H.sub.2 O                                8-OCH.sub.3                                                                              3-CF.sub.3  H       179-181                                                                       (Base)                                         8-OCH.sub.3                                                                              4-CF.sub.3  H       231-232                                                                       . 0,7 H.sub.2 O                                8-OCH.sub.3                                                                              2-CH.sub.3  H       211-214                                        8-OCH.sub.3                                                                              2,4-di-Cl   H       229-233                                        7-F        3,4,5,-tri-OCH.sub.3                                                                      H       218-221                                        7-CH.sub.3 3,4,5-tri-OCH.sub.3                                                                       H       164-167                                        H          2-CF.sub.3  H       199-201                                        H          2,6-di-F    H       228-229                                        H          2-Br        H       218-220                                        H          3-CF.sub.3  H       215-217                                                                       Or 194-195                                     8-OCH.sub.3                                                                              2-OCH.sub.3 H       206-209                                        8-OCH.sub.3                                                                              3-OCH.sub.3 H       216-219                                        8-OCH.sub.3                                                                              4-OCH.sub.3 H       230-233                                        H          4-CF.sub.3  H       oil                                            8-CH.sub.3 2-F         H       214-223                                        8-OCH.sub.3                                                                              2,6-di-F    H       oil                                            8-NO.sub.2 H           H       oil                                            8-OC.sub.2 H.sub.5                                                                       2-F         H       199-204                                        8-i-OC.sub.3 H.sub.7                                                                     2-F         H       183-186                                        7,8-OCH.sub.2 O--                                                                        2-F         H       209-213                                                                       (Base)                                         6-OCH.sub.3                                                                              2-F         H       Oil                                            7-F,8-OCH.sub.3                                                                          H           H       Oil                                            8-OCH.sub.3                                                                              4-F         2-CH.sub.3                                                                            Oil                                            8-OCH.sub.3                                                                              4-F         5-CH.sub.3                                                                            Oil                                            H          H           2-CH.sub.3                                                                            Oil                                            H          H           5-CH.sub.3                                                                            188-192                                                                       × 0,7 Acetone                            8-i-OC.sub.3 H.sub.7                                                                     2-F         2-CH.sub.3                                                                            Oil                                            8-i-OC.sub.3 H.sub.7                                                                     2-F         5-CH.sub.3                                                                            191-195                                        7,8-OCH.sub.2 O--                                                                        2-F         2-CH.sub.3                                                                            Oil                                            7,8-OCH.sub.2 O--                                                                        2-F         5-CH.sub.3                                                                            Oil                                            H          2-F         2-CH.sub.3                                                                            Oil                                            H          2-F         5-CH.sub.3                                                                            Oil                                            8-CH.sub.3 H           H       234-243                                        8-CH.sub.3,6-OCH.sub.3                                                                   2-F         H       Oil                                            7-CH.sub.3 9-Cl                                                                          H           H       Oil                                            ______________________________________                                    

R₁ -2-(R₃ -carbonyl-R₂-aminomethyl)-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives ofFormula I, wherein A and B are substituted, and R₁, R₂, R₃ and R₄ aredefined as follows:

    __________________________________________________________________________    R.sub.3                                                                              R.sub.1                                                                              R.sub.2                                                                           R.sub.4                                                                           A    B               Melting Point                      __________________________________________________________________________                                               °C.                         Thiophene-2                                                                          C.sub.2 H.sub.5                                                                      H   H   H    H    HCl        238-241                            "      CH.sub.3                                                                             C.sub.2 H.sub.5                                                                   H   H    H    Base       115-117                            "      CH.sub.3                                                                             C.sub.2 H.sub.5                                                                   H   8-OCH.sub.3                                                                        H    1,2 HCl · 0.5 Acetone                                                           102-115                            "      CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                 H   H    H    1,6 Tartrate 0.5 H.sub.2 O                                                               108-118                            "      CH.sub.3                                                                             Allyl                                                                             H   H    H    Base       112-114                            "      CH.sub.3                                                                             CH.sub.3                                                                          H   H    H    1,4 Tartrate                                                                             96-105                             Thiophene-3                                                                          C.sub.2 H.sub.5                                                                      H   H   8-OCH.sub.3                                                                        2,4-di-F                                                                           Base       Oil                                       C.sub.2 H.sub.5                                                                      H   2-CH.sub.3                                                                        8-OCH.sub.3                                                                        2-F  HCl        199-201                                   C.sub.2 H.sub.5                                                                      H   2-CH.sub.3                                                                        H    2-F  Base       Oil                                "      C.sub.2 H.sub.5                                                                      H   H   H    H    HCl        224.5-226.5                        "      C.sub.2 H.sub.5                                                                      H   H   8-OCH.sub.3                                                                        2-F  HCl        223-225                            "      Cyclopropyl-                                                                         H   H   8-OCH.sub.3                                                                        H    Base       Oil                                       methyl                                                                 "      H      H   H   H    2-F  Base       Oil                                "      C.sub.2 H.sub.5                                                                      H   H   8-OCH.sub.3                                                                        2,3-di-Cl                                                                          Base       Oil                                Furane-3                                                                             C.sub.2 H.sub.5                                                                      H   H   H    H    HCl . 0.15 H.sub.2 O                                                                     246-247                            "      C.sub.2 H.sub.5                                                                      H   H   8-OCH.sub.3                                                                        2-F  HCl        228-231                            "      n-C.sub.4 H.sub.9                                                                    H   H   8-OCH.sub.3                                                                        2-F  HCl        204-206                            "      CH.sub.3                                                                             CH.sub.3                                                                          H   8-OCH.sub.3                                                                        H    HCl        186-189                                   CH.sub.3                                                                             C.sub.2 H.sub.5                                                                   H   8-OCH.sub.3                                                                        H    1,5-Tartrate                                                                             95-110                             "      CH.sub.3                                                                             Allyl                                                                             H   8-OCH.sub.3                                                                        H    Base       Oil                                "      H      H   H   H    2-F  Base       Oil                                __________________________________________________________________________

1-methyl-2-(R₅-2-carbonyl)-aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinederivatives of Formula I wherein A and B are substituted and R₅ is asdefined as follows:

    ______________________________________                                                                        Melting Point °C.                      A        B        R.sub.5       Hydrochloride                                 ______________________________________                                        H        H        1H-pyrrol     224-229                                       8-OCH.sub.3                                                                            H        "             234-235                                       H        2-F      "             250-252                                       8-CH.sub.3                                                                             2-F      "             Oil                                           7,8-OCH.sub.2 O--                                                                      2-F      "             127-138                                                                       Base × 0.25 ether                       8-OCH.sub.3                                                                            4-OCH.sub.3                                                                            "             234-235                                       H        H        1-methylpyrrol                                                                              232-238                                       8-OCH.sub.3                                                                            H        "             233-235                                       8-OCH.sub.3                                                                            2-Br     "             176-191 (decomp.)                                                             . 0.4 H.sub.2 O.                                                              . 0.4 C.sub.2 H.sub.5 OH                      8-OCH.sub.3                                                                            2-CH.sub.3                                                                             "             210-213                                       8-OCH.sub.3                                                                            4-OCH.sub.3                                                                            "             222-224                                       7,8-OCH.sub.2 O--                                                                      2-F      "             236-249                                       H        2-F      "             174-184                                       8-CH.sub.3                                                                             2-F      "             166-169                                                                       × 0,5 acetone                           8-CH.sub.3                                                                             H        "             217-229                                                                       × 0,4 acetone                           H        H        1,2-dimethylpyrrol                                                                          Oil                                           7-n-OC.sub.3 H.sub.7                                                                   H        1-methylpyrrol                                                                              206-209                                                                       × 0,5 H.sub.2 O                         ______________________________________                                    

1-methyl-2-(R₃CO-aminomethyl)-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine derivativesof Formula I wherein A and B are substituted and R₃ CO is defined asfollows:

    ______________________________________                                                                      Melting Point °C.                        A         B       R.sub.3 CO  Dihydrochloride                                 ______________________________________                                        8-OCH.sub.3                                                                             H       picolinoyl  216-218                                                                       1.8 HCl                                         7-Br      2-Cl    "           217.5-219                                                                     1 HCl                                           H         H       nicotinoyl  211-214                                                                       . 0.13 H.sub.2 O                                8-OCH.sub.3                                                                             H       "           164-175                                                                       . 0.4 H.sub.2 O . 0,83                                                        acetone                                         7-Br      2-F     "           245-248                                         7-Br      2-Cl    "           235-238                                                                       . 0.25 H.sub.2 O                                7-Cl      2-Cl    "           231-233                                         8-OCH.sub.3                                                                             H       isonicotinoyl                                                                             231-234                                                                       . 0.4 H.sub.2 O                                 7-Br      2-Cl    "           243-244                                         ______________________________________                                    

EXAMPLE 11

A mixture of 68.4 g of the cyclization mixture of1-methyl-2-chloromethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and1-methyl-3-chloro-6-phenyl-1,2,3,4-tetrahydro-benzodiazocine, 47.2 g ofsodiumazide and 450 ml of dimethylformamide is heated to 100° C. for aperiod of four hours. Then the dimethylformamide is distilled off undervacuum and 300 ml of toluene and 200 ml of water are added to theresidue. The organic phase is separated, washed with sodium chloridesolution (10%), dried over sodium sulfate and filtered. The solvent isdistilled off and a residue of 56.1 g of raw product is obtained.

The residue is dissolved in ether and a saturated solution of hydrogenchloride in ether is added. The precipitated crystals are filtered offand are recrystallized from acetone/isopropanol. 36.7 g of1-methyl-2-azidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepinehydrochloride having a melting point of 181°-183° C. are obtained.

Analogously, R₁-2-azidomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives ofFormula X can be prepared wherein A and B are substituted and R₁ isdefined as follows:

    ______________________________________                                                                      Melting Point °C.                        A         B           R.sub.1 hydrochloride                                   ______________________________________                                        7-CH.sub.3                                                                              H           CH.sub.3                                                                              175-177                                         7-F       3,4,5-OCH.sub.3                                                                           CH.sub.3                                                                              123-126 base                                    7-CH.sub.3                                                                              3,4,5-OCH.sub.3                                                                           CH.sub.3                                                                              187-188                                         8-OCH.sub.3                                                                             H           CH.sub.3                                                                              193-194                                         7-OCH.sub.3                                                                             H           CH.sub.3                                                                              203-205                                         H         H           CH.sub.3                                                                              187-190                                         7-Cl      2-Cl        CH.sub.3                                                                              170-173                                         7-F       H           CH.sub.3                                                                              145-149                                                                       . 0.25 H.sub.2 O                                7-Cl      H           CH.sub.3                                                                              147-151.5                                       H         2-F         C.sub.2 H.sub.5                                                                       Oil*                                            7-Br      H           CH.sub.3                                                                              Oil*                                            H         2-Br        CH.sub.3                                                                              Oil*                                            7-NO.sub.2                                                                              H           CH.sub.3                                                                              Oil*                                            8-F       H           H       Oil*                                            ______________________________________                                         *IR-Spectra: 2120 cm.sup.-1 (Azid/base)                                       PerkinElmer IRSpectrophotometer 157 G                                    

EXAMPLE 12

Tablets of the following composition per tablet are prepared:

    ______________________________________                                        1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-                              5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine                                                                 25 mg                                            Corn Starch                  60 mg                                            Lactose                      130 mg                                           Gelatin (10% solution)       6 mg                                             ______________________________________                                    

The active ingredient, corn starch and lactose are worked into a pastewith a 10% gelatin solution. The paste is comminuted, the resultinggranulate is placed onto a suitable plate and is dried at 45° C.

The dried granulate is passed through a crushing apparatus and then ismixed in a mixer with the following components:

    ______________________________________                                        Talcum            5 mg                                                        Magnesium stearate                                                                              5 mg                                                        Corn Starch       9 mg                                                        ______________________________________                                    

The mixture is then pressed into tablets of 240 mg each.

EXAMPLE 13

Suppositories are prepared from the following components:

    ______________________________________                                        1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-                              5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine                                                                25 mg                                             Cocoa Butter                1975 mg                                           ______________________________________                                    

The active ingredient and the finely triturated suppository basematerial are thoroughly mixed and then are melted. From the melt whichis maintained homogeneous by means of stirring suppositories of 2 g eachare molded.

EXAMPLE 14

A solution for parenteral injection is prepared from the followingcomponents:

    ______________________________________                                        1-methyl-2-[(thiophene-2-carbonyl)-aminomethyl]-                              5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine                                                                10%                                               Dimethylacetamide           10%                                               Propylene Glycol            50%                                               Benzyl alcohol              1.5%                                              Ethanol                     10%                                               Water for injection purposes up to                                                                        1 ml                                              ______________________________________                                    

The active ingredient is dissolved in dimethylacetamide and benzylalcohol, propylene glycol, ethanol and water are added. The solution isfiltered through a filter candle and is filled into suitable ampuleswhich then are closed and sterilized.

What is claimed is:
 1. A compound selected from the group consisting of2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives of theFormula I ##STR14## wherein R₁ represents hydrogen, lower alkyl, loweralkenyl or cyclopropylmethyl,R₂ represents hydrogen, lower alkyl orlower alkenyl, R₃ represents a group of the formula a, b, c, or d##STR15## wherein R is hydrogen or C₁ -C₃ -alkyl, R₄ is hydrogen, loweralkyl, lower alkoxy, nitro or halogen, and R₄ ' is hydrogen or C₁ -C₄-alkyl, and the phenylene group A and the phenyl group B independentlyfrom each other each may be unsubstituted or be substituted by 1 to 3substituents selected from the group consisting of halogen, loweralkylthio, lower alkoxy, lower alkyl, hydroxy, nitro andtrifluoromethyl, or be substituted at two adjacent carbon atoms bymethylenedioxy or ethylenedioxy, and optical isomers andpharmaceutically-acceptable acid addition salts thereof.
 2. The compoundas defined in claim 1 wherein R₁ is methyl, R₂ is hydrogen, R₃ is agroup of Formula b.
 3. The compound as defined in claim 2 wherein R₃ is2-thiophene.
 4. The compound as defined in claim 3 wherein B isunsubstituted phenyl and A is unsubstituted phenylene or phenylenesubstituted by 7-fluoro, 7-methyl, 7-isopropyl, 6, 8-dimethyl,7,8-dimethyl, 7-methoxy, 7-n-propyloxy, 7,8-methylenedioxy,7,8-ethylenedioxy, 7-trifluoromethyl, 7-nitro, 7,8-dimethoxy,6,8-dimethoxy, 8-fluoro, 8-chloro, 8-ethyl, 8-methylthio, 8-methoxy or8-ethyloxy.
 5. The compound as defined in claim 3 wherein A isunsubstituted phenylene and B is unsubstituted phenyl, 2-fluorophenyl,3-methoxyphenyl, 2,6-dimethoxyphenyl or 3,4-dimethoxyphenyl.
 6. Thecompound as defined in claim 3 wherein A is phenylene substituted by7-fluoro, 7-bromo, 7-methyl, 8-methoxy or 7, 8-methylenedioxy and B is2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl or3,4,5-trimethoxyphenyl.
 7. The compound as defined in claim 2 wherein Ais unsubstituted phenylene or phenylene substituted by 7-fluoro,8-fluoro, 7-methyl, 8-methylthio, 7-methoxy, 8-methoxy, 8-ethyloxy,7-n-propyloxy or 7,8-methylenedioxy, and B is unsubstituted phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl or3,4,5-trimethoxyphenyl, and R₃ is a group of the formula ##STR16##wherein R₄ is 5-chloro, 4-bromo, 5-bromo, 3-methyl, 4-methyl, 5-methyl,5-ethyl, 5-methoxy or 5-ethyloxy.
 8. The compound as defined in claim 2wherein R₃ is 3-thiophene, B is unsubstituted phenyl and A is phenylenesubstituted by 7-methyl, 8-methyl, 9-methyl, 8-ethyl, 7-n-propoxy,7-isopropyl, 7-methoxy, 8-methoxy, 8-ethoxy, 8-methylthio, 6,8-dimethylor 7,8-dimethyl.
 9. The compound as defined in claim 2 wherein R₃ is agroup of the formula ##STR17## wherein R₄ is hydrogen or 2-methyl, A isunsubstituted phenylene or phenylene substituted by 7-fluoro, 7-bromo,7-chloro-8-methoxy, 7-fluoro-8-methoxy, 7-methyl, 8-methyl, 9-methyl,6-methoxy, 8-methoxy, 8-ethyloxy, 8-isopropyloxy, 8-nitro,8-methyl-6-methoxy, 7,8-methylenedioxy, 6,7-methylenedioxy, 6-hydroxy,7,8-dimethoxy and B is phenyl, 2-fluorophenyl, 2-chlorophenyl,3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 3-trifluoromethylphenyl or4-trifluoromethylphenyl.
 10. The compound as defined in claim 1 whereinR₁ is methyl, R₂ is hydrogen and R₃ is a group of formula a and A and Bare as defined in claim
 1. 11. The compound as defined in claim 10wherein R₃ is a group of the formula ##STR18## wherein R₄ is hydrogen,5-methyl or 5-nitro, A is unsubstituted phenylene or phenylenesubstituted by 7-fluoro, 7-bromo, 7-methyl, 8-ethyl, 7-isopropyl,8-methylthio, 6,8-dimethyl, 7,8-dimethyl, 7-methoxy, 6,8-dimethoxy,7,8-dimethoxy, 7-n-propyloxy, 8-methoxy, 7,8-methylenedioxy or 7-chloro,and B is phenyl, 2-chlorophenyl, 2-fluorophenyl, 3-methoxyphenyl,3,4-dimethoxyphenyl, or 3,4,5-trimethoxyphenyl.
 12. The compound asdefined in claim 10 wherein R₃ is a group of the formula ##STR19##wherein R₄ is hydrogen, 2-methyl or 5-methyl, A is unsubstitutedphenylene or phenylene substituted by 7-chloro, 8-chloro, 7-fluoro,8-fluoro, 7-fluoro-8-methoxy, 8-nitro, 7-methyl-9-chloro, 8-methylthio,7-methyl, 8-methyl, 8-methyl-6-methoxy, 8-ethyl, 7-isopropyl,7,8-dimethyl, 6,8-dimethyl, 7-methoxy, 8-methoxy, 8-ethyloxy,7-n-propyloxy, 8-isopropyloxy, 7,8-dimethoxy, 7,8-methylenedioxy, or7,8-ethylenedioxy, and B is phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 2-chlorophenyl, 2-methylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2,6-difluorophenyl,3-trifluoromethyl-4-chlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 2,3-dichlorophenyl, 3,4,5-trimethoxyphenyl or2,4-difluorophenyl.
 13. The compound as defined in claim 1 wherein R₁ ismethyl, R₂ is hydrogen, R₃ is 1H-pyrrol, 1-methylpyrrol or1,2-dimethylpyrrol, A is unsubstituted phenylene or phenylenesubstituted by 8-methyl, 8-methoxy or 7,8-methylenedioxy, and B isphenyl, 2-fluorophenyl, 2-bromophenyl, 2-methylphenyl or2-methoxyphenyl.
 14. The compound as defined in claim 1 wherein R₁ ismethyl, R₂ is hydrogen, R₃ CO is picolinoyl, nicotinoyl orisonicotinoyl, A is unsubstituted phenylene or phenylene substituted by7-bromo, 7-chloro or 8-methoxy and B is phenyl, 2-fluorophenyl or2-chlorophenyl.
 15. The compound as defined in claim 1 wherein R₂ ishydrogen, methyl, ethyl, n-propyl or allyl.
 16. The compound as definedin claim 1 wherein R₁ is hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl or cyclopropylmethyl. 17.1-methyl-2-[(thiophene-3-carbonyl)-aminomethyl]-5-(2-fluorophenyl)-1H-2,3-dihydro-1,4-benzodiazepine.18. A pharmaceutical composition comprising an analgesically effectiveamount of at least one compound as defined in claim 1 and apharmaceutically acceptable carrier.
 19. A pharmaceutical compositioncomprising an analgesically effective amount of the compound as definedin claim 17 and a pharmaceutically acceptable carrier.
 20. A method oftreating pain disorders in larger mammals which comprises administeringto a larger mammal an effective amount of a compound as defined inclaim
 1. 21. A method of treating pain disorders in larger mammals whichcomprises administering to a larger mammal an effective amount of acompound as defined in claim 17.